Project Abstract/ Summary (DRP) Breast cancers frequently harbor specific patterns of homologous recombination (HR) DNA repair defects (HRD) and/or specific patterns of genetic instability, namely chromosomal instability (CIN) and APOBEC mutagenesis. These alterations are present in a substantial proportion of breast cancers and they are enriched in metastatic disease. Biomarkers to identify these patients reliably and to define the optimal treatments for these patients are sorely needed. The Developmental Research Program (DRP) will play an important role in fostering translational research endeavors focusing on breast cancer, in particular research addressing specific patterns of DNA repair defects and/or genetic instability and their molecular basis. We will use DRP funding supplemented by a strong commitment of institutional funds to support innovative projects by new and established investigators, which are critical to the generation of new ideas in the diagnosis and treatment of this large subset of breast cancers. Our goal is to establish mechanisms for rapid funding of important new directions to accelerate progress towards the translational research goals of our SPORE. We identified a credible portfolio of promising developmental research projects, which will be competing for support once the program is established. We will request pilot project proposals with translational potential from clinical and basic investigators within the larger MSKCC community, including Rockefeller University, New York-Presbyterian Hospital and Weill Cornell Medical College of Cornell University. We will then select the most promising new projects for support after rigorous peer review by the Leadership Committee, the Internal Advisory Board and the Patient Advocates. The opinion of external reviewers will be solicited as needed. Pilot projects will be funded for 1 year, but investigators may apply for additional funding through this same competitive process the next year. Every year the Advisory and Leadership Committee members will meet to review each research project, core, career enhancement project and developmental pilot project. Committee members will be asked to assess whether any developmental project has progressed sufficiently and shown enough translational potential, so as to eclipse one of the full SPORE Research Projects. The committee members will then vote and decide whether any developmental project should be advanced to full project status. If so, the budgets will be appropriately adjusted and sent for approval with the TRP of the NCI.